Existing evidence in animals and man indicates that blockade of the CB1 receptor may offer an effective approach for combating nicotine addiction. Early studies in humans have documented these effects. This Phase I application proposes studies to design advanced CB1 pyrrolidinone antagonists toward the development of medications for smoking cessation. Our intention is to: 1) develop CB1 antagonists with limited inverse agonist or neutral antagonist activity and 2) to characterize their ability to attenuate th effects of nicotine in behavioral screening assays in rats that can be conducted within the limits of a Phase I program. We expect to forward the most successful compounds from Phase I into Phase II studies, in which we shall pursue a more detailed lead optimization program, characterize compounds for side-effect liability, and evaluate their ability to reduce addiction-related effects of nicotine in established, addiction-related, self- administration studies in nonhuman primates. Such Phase II studies should lead to one pre-clinical candidate and 2-3 back-ups.